1. Field of Invention
The present invention relates to protection of organs, tissues and organ functions during reperfusion of ischemic organs. In particular, the invention relates to prevention of functional impairment of organs caused by ischemia-reperfusion during organ transplantation, surgical operations in general, thrombolytic therapy, after major blood loss and other causes of shock and hypoperfusion of organs.
2. Description of Related Art
Prolonged ischemia followed by reperfusion induces apoptosis and inflammation leading to tissue damage and organ dysfunction, which is called ischemia-reperfusion (I/R) injury or reperfusion injury. I/R injury takes place in various clinical conditions characterized by temporary decrease or complete stop of blood flow to one or several organs (ischemia) followed by restoration of blood flow (reperfusion) (for review, see Collard, C. D. and Gelman, S., Anesthesiology 94:1133-1138, 2001)
Ischemia-reperfusion injury accompanying organ transplantations leads to dysfunction of the transplanted organ. When removed from the donor, organ transplants are perfused with cold preservation solution and subsequently either stored cold or perused with cold preservation solution. This leads to cold ischemia in the organ transplant. After transplantation to the recipient and restoration of blood flow, different extent of I/R injury develops in the organ transplant. In kidney transplantation, I/R injury and concomitant renal dysfunction leads to prolonged dependence on hemodialysis, whereas in heart liver and lung transplantations immediate proper functioning of the graft is even more important and graft dysfunction may lead to death of the patient. The continuously increasing demand of donor organs necessitates the transplantation of organs from marginal donors with impaired blood flow, including so called non-heart beating donors, whose organs are always subjected to prolonged ischemia. This further contributes to I/R injury after transplantation.
Several preservation solutions aiming at minimizing tissue damage in the organ transplants during hypothermal storage have been described. Belzer UW solution disclosed in U.S. Pat. Nos. 4,798,824 and 4,879,283 has proved useful for all organ transplants, both for in situ organ perfusion and cooling in the donor and for cold storage after the organ is harvested. While the Belzer UW solution and some other preservation solutions, such as the Euro-Collins solution (Squifflet J. P. et al., Transplant. Proc. 13:693-696, 1981), have been effective in extending the cold preservation time of organs intended for transplantation, tissue injury during cold storage and particularly during reperfusion still occurs. Therefore, reduction in I/R injury and concomitant dysfunction of organ transplants is desirable. Other preservation solutions for organ perfusion and storage are disclosed in U.S. Pat. Nos. 4,415,556, 5,145,771, 5,693,462, 6,045,990 and 6,110,504, but none of them has addressed the protection of organ transplants against I/R injury.
Another clinical condition associated with I/R injury is impairment of blood supply to a local anatomical area caused by occlusion of the blood vessel by a blood clot (thrombosis). Thrombosis of coronary and brain arteries is a leading cause of death. With thrombolytic (fibrinolytic) therapy the blood clot can be dissolved and blood flow restored, thereby preventing necrosis of the tissues. However, fibrinolytic therapy may be associated with I/R injury and concomitant organ dysfunction with potentially serious clinical complications. Other revascularisation procedures, such as percutaneous transluminal angioplasty and coronary artery bypass surgery may also lead to I/R injury (Maxwell S. R. and Lip G. Y., Int. 1. Cardiol. 58:95-117, 1997).
A further clinical condition associated with temporarily decreased blood flow to tissues and organs comprises surgical operations, such as cardiac surgery with or without cardiopulmonary bypass and angioplastic surgery. For example, cardiac and aortic surgery may result in temporary impairment of blood flow to the kidneys, which results to I/R injury and renal dysfunction.
Hypoperfusion of organs takes also place in various forms of shock, such as caused by excessive bleeding. Upon restoration of adequate blood flow, e.g. by restoring the circulating blood volume, I/R injury may take place (Collard and Gelman, 2001).
Currently, there are no effective ways in clinical practise to prevent I/R injury other than restricting the ischemia period to as short as possible (Collard and Gelman 2001). As evident from the prior art, prevention of I/R injuries would be of utmost clinical importance in the prevention of dysfunction of critical organs in various clinical conditions. Therefore, the present invention aims at providing therapeutic means to prevent I/R injury and consequent organ dysfunction.